Antibiotics inhibiting bacterial protein synthesis

Antibiotics may inhibit either the 30S or 50S ribosomal subunits in bacteria.

Aminoglycosides and Tetracyclines act on 30S ribosomes.

Aminoglycosides

They are bactericidal drugs effective against gram negative bacilli and some of them are active against Mycobacterium tuberculosis and Enterococci.

They bind to 16S rRNA of the 30S subunit near the A site through hydrogen bonds and cause misreading and premature termination of mRNA translation. As they are positively charged, they attach to the negatively charged outer membrane of bacteria leading to the formation of large pores which allows the drug to enter the bacterial cell. It requires oxygen dependent active transport mechanisms and therefore is ineffective on anaerobic bacteria. Aminoglycosides act synergistically with antibiotics which inhibit cell wall synthesis as it facilitates the entry of aminoglycoside into the cell. A classic example is the combination of gentamicin plus penicillin G to kill enterococci.

Tetracyclines

They are bacteriostatic drugs with activity against gram positive and gram negative bacteria, chlamydia, rickettsia and mycoplasma. This group includes tetracycline, chlortetracycline, doxycycline and minocycline.

They act by binding to 16S rRNA of 30S bacterial ribosome subunit and prevent binding of tRNA to the A site.

Tigecycline is a glycylcycline which is structurally similar to tetracyclines and has the same mechanism of action as tetracycline. It is used to treat MSSA and MRSA skin and subcutaneous infections, group A and B streptococci, E coli, Bacteroides fragilis and intra abdominal infections caused by facultative and anaerobic bacteria.

Chloramphenicol, Oxazolidinones, Macrolides are the major classes of drugs that inhibit 50S ribosomes

Chloramphenicol

It is a broad spectrum antibiotic effective against gram positives, gram negatives and anaerobes. It may be bacteriostatic (Salmonella typhi) or bactericidal (H influenzae, N meningitidis and S pneumoniae).

It binds to 23S rRNA of the 50S subunit thus inhibiting peptidyl transferase activity and prevents binding of tRNA to the A site of the ribosome.

Macrolides, Lincosamides and Streptogramins

All these three groups of antibiotics have similar mechanism of action on inhibiting bacterial protein synthesis. They affect translocation by inhibiting the peptidyl transferase activity of 23S rRNA of the 50S ribosomal subunit. This causes premature detachment of incomplete peptide chains.

Macrolides are wide spectrum bacteriostatic drugs that include Azithromycin, Erythromycin and Clarithromycin. Azithromycin and Erythromycin are used to treat Chlamydia trachomatis, respiratory tract infections caused by Legionella, Mycoplasma, Chlamydia pneumoniae and S pneumoniae. Clarithromycin is used in the treatment of H pylori and Mycobacterium avium intracellulare.

Lincosamides include Lincomycin, Pirlimycin and Clindamycin. They are bacteriostatic drugs used to treat gram positive bacteria only as they cannot pass through the pores of gram negative bacteria.

Streptogramins include Quinipristin/Dalfopristin,Pristinamycin and Virginiamycin. They are used in the treatment of VRSA(Vancomycin resistant S. aureus) and VRE (Vanmcomycin resistant enterococci).

Linezolid (Oxazolidinones)

It is effective against VRE, MRSA and MRSE (Methicillin resistant S.epidermidis) and penicillin resistant pneumococci. It interferes with protein synthesis at 23S rRNA of the 50S subunit and inhibits peptidyl t RNA.

Retapamulin

It is a newer antibiotic used topically for skin infections caused by streptococci (impetigo) and staphylococci. It binds to 23S rRNA of the 50S subunit and blocks the attachment of the donor tRNA.

Antibiotics Inhibiting Bacterial DNA Replication

Quinolones are included in this group. They are bactericidal drugs including Ofloxacin, Levofloxacin, Ciprofloxacin, Norfloxacin etc. effective against organisms causing lower respiratory tract infections. gastrointestinal infections, UTIs and skin, bone and soft tissue infections.

They inhibit the enzyme DNA gyrase in bacteria also called topoisomerase IV. They specifically target “A” subunit of the enzyme and interfere with strand cutting and resealing function and hence inhibit DNA replication.

Antibiotics That Interfere With Folic Acid Metabolism

This group includes sulfonamides and trimethoprim. In combination these drugs are effective in the treatment of Toxoplasmosis, Pneumocystis jiroveci pneumonia, UTIs and Shigellosis. Each of these drugs inhibit distinct steps in folic acid metabolism leading to inhibition of tetrahydrofolate synthesis. Tetrahydrofolate is essential for nucleic acid synthesis in bacteria.

Sulfonamides are structural analogues for PABA (para aminobenzoic acid) which is a substrate for the enzyme dihydropteroate synthase. Thus sulfonamides competitively inhibit the enzyme.

While trimethoprim inhibits dihydrofolate reductase which is a step at a later stage in folic acid synthesis.

The combination of sulfonamides with trimethoprim shows synergy in inhibiting bacterial growth and also lowers the emergence of resistant bacterial mutants.

Antibiotics Inhibiting mRNA Synthesis

Rifampin and Rifabutin belong to this group. They block mRNA synthesis by bacterial RNA polymerase.

Rifampin is used in the treatment of tuberculosis, S.epidermidis prosthetic valve endocarditis, prophylaxis of N.meningitidis and H. influenzae meningitis. Rifabutin is used in the prophylaxis of M.avium-intracellulare infections in AIDs patients.

Antibiotics Acting on Bacterial Cell Membrane

This group includes Polymyxins and Daptomycin.

Polymyxins B and E (colistin) are effective against gram negative bacilli. They bind to lipopolysaccharides in the outer membrane of gram negative bacteria and act as a cationic detergent to disrupt the phospholipid structure of the cell membrane.

Daptomycin (Cubicin) is a lipopeptide antibiotic effective against a wide range of gram positive cocci such as S.aureus and S.epidermidis including resistant strains like MRSA, MRSE and VRSA; Enterococcus faecalis and faecium including resistant strains like VRE. Because of its efficacy against resistant bacterial strains it is used in the treatment of skin and soft tissue infections caused by these bacteria and sometimes in endocarditis and sepsis. It inserts into the bacterial cell membrane, creating holes which cause ions to leak from the cell causing rapid depolarization and resultant inhibition of protein and nucleic acid synthesis.